During the course of chemotherapy of human cancers, variants which are resistant to multiple drugs frequently arise. We have been investigating the genetic and biochemical basis for this pleiotropic resistant of human tumor cells to chemotherapeutic agents. A model system using the cultured KB cell, a human tumor cell line, has been developed in which mutant cells selected for resistance to high levels of colchicine have also been found to be resistant to adriamycin, vincristine, vinblastine, puromycin and actinomoycin-D. These drugs are chemically and mechanistically unrelated to each other but may share a common mode entry, metabolism or exit fromcells. The mechanism of this multiple drug resistance is being studied by analysis of cell surface glycoproteins which might be involved in uptake of the drugs, dominance and complementation analysis of mutant cell lines and gene transfer of drug resistance genes from human tumor cells.